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A Rare Syndrome with Alemtuzumab, Review of Monitoring Protocol

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A Rare Syndrome with Alemtuzumab, Review of Monitoring Protocol Open Access Case Report DOI: 10.7759/cureus.5715 Idiopathic Thrombocytopenic Purpura: A Rare Syndrome with Alemtuzumab, Review of Monitoring Protocol Deepika Sarvepalli 1 , Mamoon Ur Rashid 2 , Waqas Ullah 3 , Yousaf Zafar 4 , Muzammil Khan 5 1. Internal Medicine, Guntur Medical College, Guntur, IND 2. Internal Medicine, AdventHealth, Orlando, USA 3. Internal Medicine, Abington Hospital - Jefferson Health, Abington, USA 4. Internal Medicine, University of Missouri - Kansas City School of Medicine, Kansas City, USA 5. Internal Medicine, Khyber Teaching Hospital, Peshawar, PAK Corresponding author: Deepika Sarvepalli, [email protected] Abstract Alemtuzumab, a humanized monoclonal antibody that targets surface molecule CD52, causes rapid and complete depletion of circulating T- and B-lymphocytes through antibody-dependent cell-mediated and complement-mediated cytotoxicity. Alemtuzumab has demonstrated superior efficacy compared to subcutaneous interferon beta-1a (SC IFNB-1a) in patients with multiple sclerosis (MS). Alemtuzumab treatment causes a rare and distinct form of secondary immune thrombocytopenic purpura (ITP), characterized by delayed onset, responsiveness to conventional therapies, and prolonged remission following treatment. In phase two and three clinical trials, the incidence of ITP was higher with alemtuzumab treatment compared to the patients receiving SC IFNB-1a. Here we report a case of ITP occurring two years after the first treatment with alemtuzumab. The patient recovered completely after a timely diagnosis and adequate treatment. Rigorous patient education and careful complete blood count (CBC) monitoring by the physician are critical for early identification and treatment of this potentially fatal disorder. Categories: Internal Medicine, Neurology, Other Keywords: alemtuzumab, itp, multiple sclerosis, alemtuzumab autoimmunity, platelet disorders Introduction Alemtuzumab is a humanized monoclonal antibody that targets surface molecule CD52, expressed at high levels on T- and B-lymphocytes, and at very low levels on natural killer cells, monocytes, and macrophages. Alemtuzumab causes rapid and complete depletion of circulating T- and B-lymphocytes through antibody- dependent cell-mediated and complement-mediated cytotoxicity [1]. In November 2014, alemtuzumab (Lemtrada®, Sanofi Genzyme, Cambridge, MA, USA) was approved by the Food and Drug Administration (FDA) for the treatment of active relapsing remitting multiple sclerosis Received 09/13/2019 Review began 09/16/2019 (RRMS). Alemtuzumab has demonstrated superior efficacy (low relapse rates, improved disability, and Review ended 09/16/2019 decreased brain volume loss) compared to subcutaneous interferon beta-1a (SC IFNB-1a) in patients with Published 09/20/2019 RRMS [2-3]. © Copyright 2019 Sarvepalli et al. This is an open access Common adverse effects (AEs) of alemtuzumab treatment include infections, infusion reactions, and article distributed under the terms of the secondary autoimmune reactions [4-6]. Autoimmune AEs consisted of thyroid disorders (39% in CARE-MS Creative Commons Attribution License six year follow-up study), immune thrombocytopenic purpura (ITP) (2.6% in CARE-MS six year follow-up CC-BY 3.0., which permits unrestricted use, distribution, and reproduction in any study), and autoimmune renal disease (0.2% in CARE-MS six year follow-up study) that occurred years after medium, provided the original author and first treatment [6]. source are credited. Immune thrombocytopenic purpura is a bleeding disorder characterized by isolated low platelet count not associated with a systemic disease. It can be primary (no predisposing agent) or secondary to a predisposing factor such as drugs, infections, autoimmune disorders, or neoplasms. Alemtuzumab treatment causes a distinct form of secondary ITP, characterized by delayed onset, responsiveness to conventional therapies, and prolonged remission following treatment [7]. Here we report a case of ITP occurring two years after the first treatment with alemtuzumab. Case Presentation A 45-year-old female with a history of multiple sclerosis (MS) was admitted to the hospital for low platelet count, after being referred by her primary care physician (PCP). She was placed on alemtuzumab as a part of the treatment for MS. Treatment was initiated two years ago, and she received two doses one year apart, with the last dose administered one year ago. The patient was continuously monitored with monthly complete blood count (CBC). On physical examination, the patient had mucocutaneous manifestations of How to cite this article Sarvepalli D, Rashid M, Ullah W, et al. (September 20, 2019) Idiopathic Thrombocytopenic Purpura: A Rare Syndrome with Alemtuzumab, Review of Monitoring Protocol. Cureus 11(9): e5715. DOI 10.7759/cureus.5715 thrombocytopenia; petechia on the chest and bruises on upper limbs were noticed. The patient did not have a history of Wiskott-Aldrich syndrome, thrombocytopenia - absent radius syndrome, May-Hegglan anomaly, gray platelet syndrome, Upshaw-Shulman syndrome, or Bernard-Soulier syndrome. On the first day of admission, the patient had a platelet count of only 3000/μL. Her medical records from the last three months showed a serial decline of platelet count. Further investigations were done on the patient, in search for the etiology of thrombocytopenia. The patient did not have any signs of thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and disseminated intravascular coagulation (DIC) as evidenced by the absence of schistocytes on peripheral smear, normal lactate dehydrogenase (LDH), and normal renal functions and normal prothrombin time/activated partial thromboplastin time (PT /aPTT). Moreover, patient‘s home medications were reviewed, including ampura, oxybutynin, donepezil, baclofen which were not associated with thrombocytopenia. Other labs such as vitamin B12 level, thyroid stimulating hormone (TSH), antinuclear antibody (ANA), rheumatoid factor (RF), human immunodeficiency virus (HIV), Ebstein-Barr virus (EBV), hepatitis serology were unremarkable. After excluding other causes, the patient was treated for ITP secondary to alemtuzumab, with prednisone 1 mg/kg. Soon, the patient showed a good response to treatment; platelet count increased, and bruises and petechiae resolved within a few days. Discussion The ITP syndrome is recognized by antibody and cell-mediated platelet destruction and suppression of platelet production, which may occur without any predisposing factor (primary ITP) or secondary due to conditions, including autoimmune disorders, neoplasms, congenital immune deficiencies, drugs, and infections. The diagnostic criteria of ITP, outlined by an international working group, include either a confirmed platelet count of ≥50 × 109/L and <100 × 109/L on ≥ two consecutive occasions over one month, or a confirmed platelet count <50 × 109/L on ≥ two consecutive occasions over any period of time; and normal hemoglobin (Hb), normal white blood cell (WBC) count, no splenomegaly, normal peripheral smear except for low platelets, and no evidence of an alternative nonautoimmune etiology of thrombocytopenia [8]. In our case, ITP was thought to be secondary to alemtuzumab treatment as no other etiology was found, and a normal platelet count was documented before starting the medication. The incidence of ITP in patients treated with alemtuzumab is higher compared to the general population and patients receiving SC IFNB-1a. During the CAMMS223 phase II clinical trial [6], 334 patients were tested for the development of ITP after therapy. Patients were randomly assigned to either alemtuzumab or SC IFNB-1a and followed up for 4.5 years. While ITP was observed in 2.8% (six out of 216) of the people treated with alemtuzumab, it was noticed in only 0.9%(one out of 107) of the patients on SC IFNB-1a [6]. Moreover, the occurrence of ITP with alemtuzumab was dose-dependent (1.9% in 12 mg/d vs. 3.7% in 24 mg/d). The overall incidence rate of ITP in the three cohorts: alemtuzumab 12 mg/d, alemtuzumab 24 mg/d, and SC IFNB-1a were 4.2, 8.0, and 2.7 per 1000 person-years, respectively [6]. Alemtuzumab-induced ITP is distinct from both drug-induced ITP (DITP) and adult primary ITP in terms of the onset and course of the disease. DITP typically occurs within days of exposure to the drug and requires the presence of the drug in the blood. DITP usually resolves within days after discontinuing the drug. In contrast, alemtuzumab-associated ITP appears in a delayed fashion and can occur months to years after the last dose of the medication [7]. A point worth mentioning here is the unique dosing schedule of alemtuzumab in the treatment of RRMS. The recommended schedule comprises intravenous infusion of 12 mg of alemtuzumab on each of five consecutive days (total dose of 60 mg) and on each of three consecutive days (36 mg total dose) 12 months later. During the clinical development program, alemtuzumab-induced ITP occurred at a median time of 10.5 months after the last dose, and all the cases happened within 48 months after the last infusion of the medication [9-10]. This delayed pattern of alemtuzumab autoimmunity strikes a resemblance with autoimmune disorders occurring in the setting of antiretroviral therapy in HIV- infected patients and autologous hematopoietic stem cell transplantation, suggesting a likely disorder of lymphocyte repopulation [11-14]. In adults, primary ITP typically runs a chronic course, and only 10% of the patients experience durable remission
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